Antipsychotic agents, compositions and method of use

ABSTRACT

This invention relates to compounds of the formula ##STR1## wherein X, Y, Z, m, n and p are as defined within, pharmaceutical compositions containing these compounds and to their use as antipsychotic agents, particularly in the treatment of schizophrenia. Depot derivatives of the compounds are useful for providing long acting effects of the compounds.

This application is a division of application Ser. No. 08/921,480 filedSep. 2, 1997, now U.S. Pat. No. 5,852,022, which is a continuation ofapplication Ser. No. 08/470,400 filed Jun. 6, 1995, now abandoned.

This invention relates to heteroarylpiperazines having antipsychoticactivity and to their use as antipsychotic drugs.

The therapeutic treatment of schizophrenic patients by administration ofneuroleptic drugs, such as chlorpromazine, haloperidol, sulpiride, andchemically closely related compounds, is widespread. While control ofschizophrenic symptoms has been successful, treatment with these drugsdoes not cure the psychotic patient, who will almost certainly relapseif medication is discontinued. There exists a continuing need in the artfor antipsychotic drugs for the treatment of psychoses.

Moreover, some of the known neuroleptics produce unwanted side effects.For example, the side effects of many antipsychotic drugs include theso-called extrapyramidal symptoms, such as rigidity and tremor,continuous restless walking, and tardive dyskinesia which causes facialgrimacing, and involuntary movements of the face and extremities.Orthostatic hypotension is also common. Thus, there also exists a needin the art for antipsychotic drugs that produce fewer or less severemanifestations of these common side effects.

In addition, because of the frequent long term administration ofneuroleptics and the problems with patient compliance, there is afurther need in the art for long lasting neuroleptics, which can beformulated into sustained release depot preparations, without the sideeffects previously mentioned.

This invention relates to a compound of the formula ##STR2## wherein Xis --OH, --OC(═O)(C₁ -C₁₈)alkyl, --OC(═O)(C₆ -C₁₀)aryl, --OC(═O)(C₁-C₁₂)alkyl(C₆ -C₁₀)aryl, --OC(═O)NH(C₁ -C₁₈)alkyl, --OC(═O)(C₁-C₁₂)alkyl(C₃ -C₈)cycloalkyl, --OC(═O)O(C₁ -C₁₈)alkyl, or --OC(═O)--(C₃-C₁₂)cycloalkyl;

Y is hydrogen, halogen, trifluoromethyl, (C₁ -C₆)alkoxy, cyano or nitro;

Z is O or NR₁ ;

R₁ is hydrogen, (C₁ -C₆)alkyl, formyl, --C(═O)(C₁ -C₁₈)alkyl, or--C(═O)O(C₁ -C₁₈)alkyl;

m is 1, 2, 3 or 4;

n is 1 or 2; and

p is 1 or 2; and

its pharmaceutically acceptable acid addition salts; pharmaceuticalcompositions containing these compounds and their use as antipsychoticagents, particularly in the treatment of schizophrenia. The compounds ofthe invention are atypical antipsychotic agents.

This invention also provides compounds which are suitable for acylationwith (C₁ -C₁₈)carboxylic acids or reactive functional derivativesthereof to form highly lipophilic esters, amides and carbamates, whichcompounds are also compounds of this invention. Such selected compoundspossess a hydroxyl group attached to either an aromatic carbon atomcapable of forming the highly lipophilic esters of the invention or asecondary nitrogen atom including the nitrogen at the 1-position of anindazole ring system capable of forming the highly lipophilic amides ofthe invention. The secondary nitrogen atom may alternatively be acylatedwith a (C₁ -C₁₈)alkoxy-carbonyl chloride to form a highly lipophiliccarbamate derivative of the invention.

The invention also provides for the highly lipophilic compounds whichprovide long acting pharmaceutical effects when administered in the formof depot preparations.

This invention also provides a pharmaceutical composition, whichcomprises a compound of the invention and a pharmaceutically acceptablecarrier therefor. In one embodiment of the invention, the pharmaceuticalcomposition is an antipsychotic composition comprising a compound of theinvention in an amount sufficient to produce an antipsychotic effect.

In addition, this invention provides a method of treating psychoses,which comprises administering to a patient a pharmaceutically effectiveamount of a compound of the invention.

Further, this invention provides a method of sustained release of apharmaceutically effective amount of a lipophilic compound of theinvention in the form of a depot preparation.

Unless otherwise stated or indicated, the following definitions shallapply throughout the specification and the appended claims.

The term (C₁ -C₁₈)alkyl shall mean a straight or branched alkyl group,for example, methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl,isobutyl, sec-butyl and straight and branched chain pentyl, hexyl,heptyl, decyl, undecyl, dodecyl, etc. up to an 18 carbon chain length.

The term halo or halogen shall mean fluorine, chlorine, bromine oriodine.

The term (C₃ -C₁₂)cycloalkyl shall mean monocyclo and polycyclo alkylrings such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, adamantyl, norbornyl and the like.

The term (C₆ -C₁₀)aryl shall mean aromatic carbocyclic rings such asbenzene and naphthalene.

Throughout the specification and the appended claims, a given formula orname shall encompass all stereo, optical, enantiomeric and tautomericisomers where such isomers exists.

In one class of compounds of this invention is a compound of the formula##STR3## wherein X is --OH, --OC(═O)(C₁ -C₁₈)alkyl, --OC(═O)NH(C₁-C₁₈)alkyl, --OC(═O)O(C₁ -C₁₈)alkyl or --OC(═O)--(C₃ -C₁₂)cycloalkyl;

Y is hydrogen, halogen, trifluoromethyl, (C₁ -C₆)alkoxy, cyano or nitro;

Z is O or NR₁ ;

R₁ is hydrogen, (C₁ -C₆)alkyl, formyl, --C(═O)(C₁ -C₁₈)alkyl or--C(═O)O(C₁ -C₁₈)alkyl;

m is 1, 2, 3 or 4;

n is 1 or 2; and

p is 1 or 2; and

its pharmaceutically acceptable acid addition salts.

In a preferred embodiment of this class is a compound of the formula##STR4## wherein X is --OH, --OC(═O)(C₁ -C₁₈)alkyl, --OC(═O)NH(C₁-C₁₈)alyl, --OC(═O)O(C₁ -C₁₈)alkyl or --OC(═O)--(C₃ -C₁₂)cycloalkyl;

Y is hydrogen or halogen;

m is 1, 2, 3 or 4; and

p is 1; and

its pharmaceutically acceptable acid addition salts.

More preferably, m is 3 and Y is 4-fluoro.

Most preferably X is 6-hydroxy, 6--OC(═O)NHbutyl, 6--OC(═O)Ohexyl,6--OC(═O)nonyl, or 6--OC(═O)adamantyl; and its pharmaceuticallyacceptable acid addition salts.

In another preferred embodiment of this class is a compound of theformula ##STR5## wherein X is --OH, --OC(═O)(C₁ -C₁₈)alkyl,--OC(═O)NH(C₁ -C₁₈)alkyl, --OC(═O)O(C₁ -C₁₈)alkyl or --OC(═O)--(C₃-C₁₂)cycloalkyl;

Y is hydrogen or halogen;

R₁ is hydrogen, (C₁ -C₆)alkyl, formyl, --C(═O) (C₁ -C₁₈)alkyl, or--C(═O)O (C₁ -C₁₈)alkyl;

m is 1, 2, 3 or 4; and

p is 1; and

its pharmaceutically acceptable acid addition salts.

More preferably, m is 3 and Y is 4-fluoro.

Most preferably, X is 6-hydroxy, 6--OC(═O)NHbutyl, 6--OC(═O)Ohexyl,6--OC(═O)nonyl, or 6--OC(═O)adamantyl; and R₁ is hydrogen or--C(═O)nonyl; and its pharmaceutically acceptable acid addition salts.

In another class of compounds of this invention is a compound of theformula ##STR6## wherein X is --OH, --OC(═O)(C₁ -C₁₈)alkyl,--OC(═O)NH(C₁ -C₁₈)alkyl, --OC(═O)O(C₁ -C₁₈)alkyl or --OC(═O)--(C₃-C₁₂)cycloalkyl;

Y is hydrogen, halogen, trifluoromethyl, (C₁ -C₆)alkoxy, cyano or nitro;

Z is O or NR₁ ;

R₁ is hydrogen, formyl, (C₁ -C₆)alkyl, --C(═O)(C₁ -C₁₈)alkyl, or--C(═O)O(C₁ -C₁₈)alkyl;

m is 1, 2, 3 or 4; and

p is 1 or 2; and

its pharmaceutically acceptable addition salts.

In a preferred embodiment of this class is a compound of the formula##STR7## wherein X is --OH, --OC(═O)(C₂ -C₁₈)alkyl, --OC(═O)NH(C₁-C₁₈)alkyl, --OC(═O)O(C₁ -C₁₈)allyl or --OC(═O)--(C₃ -C₁₂)cycloalkyl;

Y is hydrogen or halogen;

m is 1, 2, 3 or 4; and

p is 1; and

its pharmaceutically acceptable acid addition salts.

More preferably, m is 3 and Y is 4-fluoro.

Most preferably, X is 6-hydroxy, 6--OC(═O)NHbutyl, 6--OC(═O)Ohexyl,6--OC(═O)nonyl, or 6--OC(═O)adamantyl; and its pharmaceuticallyacceptable acid addition salts.

In another preferred embodiment of this class are compounds of theformula ##STR8## wherein X is --OH, --OC(═O)(C₁ -C₁₈)alkyl,--OC(═O)NH(C₁ -C₁₈)alkyl, --OC(═O)O(C₁ -C₁₈)alkyl or --OC(═O)--(C₃-C₁₂)cycloalkyl;

Y is hydrogen or halogen;

R₁ is hydrogen, (C₁ -C₆)alkyl, formyl, --C(═O) (C₁ -C₁₈)alkyl, or--C(═O)O(C₁ -C₁₈)alkyl;

m is 1, 2, 3 or 4;

n is 1; and

p is 1 or 2; and

its pharmaceutically acceptable acid addition salts.

More preferably, m is 3 and Y is 4-fluoro.

Most preferably, X is 6-hydroxy, 6--OC(═O)NHbutyl, 6--OC(═O)Ohexyl,6--OC(═O)nonyl, or 6--OC(═O)adamantyl; and R₁ is hydrogen or--C(═O)nonyl; and its pharmaceutically acceptable acid addition salts.

Nonlimiting examples of compounds of the invention include:

3-[1-(4'-Fluorobenzoyl)propyl4-piperazinyl]-6-hydroxy-1,2-benzisoxazole

3-[1-(4'-Fluorobenzoyl)propyl-4-piperazinyl]-5-hydroxy-1,2-benzisoxazole

3-[1-(4'-Fluorobenzoyl)propyl-4-piperazinyl]-4-hydroxy-1,2-benzisoxazole

3-[1-(4'-Fluorobenzoyl)propyl-4-piperazinyl]-7-hydroxy-1,2-benzisoxazole

3-[1-(4'-Fluorobenzoyl)propyl-4-piperazinyl]-6-hydroxy-1,2-benzisoxazolehydrobromide

3-[1-(4'-Fluorobenzoyl)propyl-4-piperazinyl]-6-hydroxy-1,2-benzisoxazolehydrochloride

3-[1-(4'-Fluorobenzoyl)butyl-4-piperazinyl]-6-hydroxy-1,2-benzisoxazole

3-[1-(4'-Fluorobenzoyl)ethyl-4-piperazinyl]-6-hydroxy-1,2-benzisoxazole

3-[1-(4'-Fluorobenzoyl)methyl-4-piperazinyl]-6-hydroxy-1,2-benzisoxazole

Butyl carbamic acid3-[4-[4-(4-fluorophenyl)4-oxo-butyl]-piperazin-1-yl]-1,2-benzisoxazol-6-ylester

Hexyl carbamic acid3-[4-[4-(4-fluorophenyl)-4-oxo-butyl]-piperazin-1-yl]-1,2-benzisoxazol-6-ylester

Dodecyl carbamic acid3-[4-[4-(4-fluorophenyl)-4-oxo-butyl]-piperazin-1-yl]-1,2-benzisoxazol-6-ylester

Octadecyl carbamic acid3-[4-[4-(4-fluorophenyl)4-oxo-butyl]-piperazin-1-yl]-1,2-benzisoxazol-6-ylester

Decanoic acid3-[4-[4-(4-fluorophenyl)-4-oxo-butyl]-piperazin-1-yl]-1,2-benzisoxazol-6-ylester

Dodecanoic acid3-[4-[4-(4-fluorophenyl)4-oxo-butyl]-piperazin-1-yl]-1,2-benzisoxazol-6-ylester

Hexadecanoic acid3-[4-[4-(4-fluorophenyl)4-oxo-butyl]-piperazin-1-yl]-1,2-benzisoxazol-6-ylester

Octadecanoic acid3-[4-[4-(4-fluorophenyl)4-oxo-butyl]-piperazin-1-yl]-1,2-benzisoxazol-6-ylester

Adamantane-1-carboxylic acid ³ -[⁴ -[⁴-(4-fluorophenyl)4-oxo-butyl]-piperazin-1-yl]-1,2-benzisoxazol-6-ylester

Cyclohexylhexanoic acid3-[4-[4-(4-fluorophenyl)4-oxo-butyl]-piperazin-1-yl]-1,2-benzisoxazol-6-ylester

Cyclohexylcarboxylic acid3-[4-[4-(4-fluorophenyl)-4-oxo-butyl]-piperazin-1-yl]-1,2-benzisoxazol-6-ylester

Carbonic acid(3-[4-[4-(4-fluorophenyl)4-oxo-butyl]piperazin-1-yl]-1,2-benzisoxazol-6-yl)esterhexyl ester

Carbonic acid(3-[4-[4-(4-fluorophenyl)-4-oxo-butyl]piperazin-1-yl]-1,2-benzisoxazol-6-yl)esterdodecyl ester

Carbonic acid(3-[4-[4-(4-fluorophenyl)-4-oxo-butyl]piperazin-1-yl]-1,2-benzisoxazol-6-yl)esteroctadecyl ester

3-[1-(4'-Fluorobenzoyl)propyl-4-homopiperazinyl]-6-hydroxy-1,2-benzisoxazole

Butyl carbamic acid3-[4-[4-(4-fluorophenyl)-4-oxo-butyl]-homopiperazin-1-yl]-1,2-benzisoxazol-6-ylester

Decanoic acid3-[4-[4-(4-fluorophenyl)-4-oxo-butyl]-homopiperazin-1-yl]-1,2-benzisoxazol-6-ylester

Carbonic acid(3-[4-[4-(4-fluorophenyl)-4-oxo-butyl]homopiperazin-1-yl]-1,2-benzisoxazol-6-yl)esterhexyl ester

3-[1-(4'-Fluorobenzoyl)propyl-piperazinyl]-6-hydroxy-1H-indazole

3-[1-(4'-Fluorobenzoyl)propyl-4-piperazinyl]-6-hydroxy-1H-indazolehydrochloride

Butyl carbamic acid3-[4-[4-(4-fluorophenyl)-4-oxo-butyl]-piperazin-1-yl]-1H-indazol-6-ylester

Octadecanoic acid3-[4-[4-(4-fluorophenyl)-4-oxo-butyl]-piperazin-1-yl]-1H-indazol-6-ylester

Carbonic acid(3-[4-[4-(4-fluorophenyl)4-oxo-butyl]-piperazin-1-yl]-1H-indazol-6-yl)esteroctadecyl ester

The compounds of the invention can be synthesized using one or more ofthe following general procedures described below.

Throughout the description of the synthetic procedures, the notations X,Y, m, n and p have the respective meanings given above unless otherwisestated or indicated, R is (C₁ -C₁₈)alkyl, (C₆ -C₁₀)aryl, (C₁-C₁₂)alkylaryl, (C₁ -C₁₂)alyky(C₃ -C₈)cycloalkyl or (C₃ -C₁₂)cycloalkyl,and other notations have the respective meanings defined in their firstappearances.

More particularly, as shown in Reaction Scheme A, the benzoxazoles areprepared from the chloro compound of Formula III, where X is alkoxy, isreacted with the cyclic amine of the formula IV to form the compound ofFormula V where X is alkoxy.

The reaction is typically carried out neat in a sealed tube or undernitrogen at a temperature of from about 100° C. to about 200° C.,preferably from about 120° C. to about 180° C., most preferably fromabout 130° C. to about 150° C. for from about 0.5 hour to about 100hours, preferably from about 0.5 hours to about 8 hours, most preferablyfrom about 0.45 hours to about 6 hours.

The compound of Formula V is then reacted with the haloalkylphenonecompound of Formula VI to provide the compound of Formula VII wherein Xis alkoxy. The reaction can be carried out in a polar non-protic organicsolvent such as, for example, acetonitrile, at a temperature of fromabout 0° C. to about 120° C., preferably from about 60° C. to about 100°C., most preferably at about 80° C. for from about 0.5 hours to about 24hours, preferably for from about 1 hour to about 12 hours, mostpreferably for about 4 to 6 hours. The reaction is generally carried outin the presence of a base such as potassium or sodium carbonate and acatalyst such as potassium iodide.

The indazoles are prepared as shown in Reaction Scheme B, starting fromthe appropriate acetophenone of Formula IX wherein X is alkoxy which isoxidized to the corresponding carboxylic acid of Formula X wherein X isalkoxy under known conditions such as in the presence of sodiumhydroxide and bromine. ##STR9##

The acid of Formula X wherein X is alkoxy is then treated with sulfonylchloride and p-toluenesulfonhydrazide under known conditions to form thehydrazide of Formula XI which is further treated with sulfonyl chlorideunder known conditions to yield the chlorotosylhydrazone of Formula XIIwherein X is alkoxy.

The chlorotosylhydrazone of Formula XII wherein X is alkoxy is reactedwith the appropriate phenylpiperazinyl ketone of Formula XIII (preparedfrom the appropriate haloalkylphenone and piperazine under knownconditions) to yield the hydrazono compound of Formula XIV wherein X isalkoxy. The reaction is typically carried out in an organic solvent atfrom about 0° C. to about 50° C., preferably from about 10° C. to about35° C., most preferably at about room temperature.

The compound of Formula XIV is then heated in a polar non-protic solventsuch as dimethylformamide for from about 1 hour to about 24 hours, morepreferably from about 2 hours to about 12 hours, most preferably fromabout 3 hours to about 6 hours at a temperature of from about 35° C. toabout 125° C., more preferably from about 50° C. to about 100° C., mostpreferably at about 90° C. to yield the compound of Formula XV.

The compound of Formula XV is heated in the presence of hydrochloricacid to form the compound of Formula XVI wherein X is alkoxy.

The compound of Formula XVI is alkylated under known conditions, such aswith dimethylsulfate in the presence of a base such as potassiumcarbonate in a non-protic organic solvent to form the compound ofFormula XVII.

The compounds of Formula VII and XVII when X is alkoxy can be treatedwith acid such as, for example, 48% hydrobromic acid to yield thecorresponding hydroxy compounds of Formula VIII and XVIII. The reactionis typically carried out at reflux for from about 1 hour to about 12hours, preferably from about 2 hours to about 4 hours. ##STR10##

The hydroxy compounds of Formula VIII and XVIII are treated with theappropriate isocyanate, carbamoylchloride or carbonyldimidazole and anamine to obtain the corresponding compounds of Formula XIX and XX whereR is (C₁ -C₁₈)alkyl or aryl(C₁ -C₁₀)alkyl. The reaction is carried outin an inert organic solvent such as, for example, ethyl acetate for fromabout 0.5 hours to about 24 hours, optionally in the presence of acatalyst such as, for example, copper(I)chloride.

Additionally, the hydroxy compounds of Formula VIII and XVIII aretreated with an alkyl, aryl or aralkylcarboxylic acid halide, such asfor example, adamantanecarbonyl chloride or decanoyl chloride, underbasic conditions known in the art to yield the corresponding alkoxy,aryloxy or aralkyloxy compounds of Formula XXI and XXII.

The hydroxy compounds of Formula VIII and XVIII are also reacted underbasic conditions known in the art with the appropriate chloroformate toyield the carbonate compounds of Formula XXIII and XXIV.

In the case of the indazoles, the nitrogen at the 1-position of theindazole can also be substituted by means known in the art.

The preparation of the starting materials is known in the art. Forexample, the preparation of the compounds of Formula III is disclosed inWO 9412495A1.

Selected compounds of the invention possess a hydroxyl or amine groupattached to either an aliphatic or aromatic carbon capable of formingthe highly lipophilic esters or amides of this invention The hydroxygroup may alternatively be acylated with a (C₁ -C₁₈) alkoxycarbonylchloride to form a highly lipophilic carbonate derivative or with a (C₁-C₁₈) carbamoylhalide to form a highly lipophilic carbamate derivative.Representatives of such alcohols and amines and their highly lipophilicderivatives are found in the Examples of this invention.

It is known in the art that long acting derivatives of drugs may beobtained by such transformation. European Patent Publication No. 260,070discloses the prolonged action of haloperidol decanoate ester.International Publication No. WO 92/06089 discloses sustained releaseamide derivatives of sertindole.

The compounds of the present invention are useful for treating psychosesby virtue of their ability to elicit an antipsychotic response inmammals. In particular, the present compounds are potent atypicalantipsychotic agents, i.e. compounds which display a D₂ /5-HT₂ affinityratio of greater than 1. The compounds of the invention further show areduced potential for extra pyramidal side effects (EPS) as evidenced bya large difference in ED₅₀ for the Climbing Mouse Assay (CMA) and theApomorphine Induced Stereotypy in Rats Test (APO-S).

It is known that it is possible to predict antipsychotic efficacy andpotential side effect liability by observing the electrophysiologicalprofile of a drug on the dopamine (DA) neurons in the mesolimbic (A10)and nigrostriatal (A9) regions, respectively, of the rat brain. Thus, ithas been shown by utilizing extracellular single unit recordingtechniques that all compounds that were effective antipsychotics bothclassic and atypical, would cause, upon repeated administration, a tonicdepolarization inactivation of the A10 DA neurons. Such a result wouldsupport the hypothesis that the symptoms of schizophrenia arepredominantly due to excess DA activity in the mesolimbic area of thebrain. However, it has also been shown that classic antipsychotics,those known to have EPS liability, such as haloperidol, wouldadditionally cause a depolarization inactivation of the DA neurons inthe A9 area of the brain. As this area of the brain has been linked tomotor function, the inhibition of these neurons provided a rationale forthe EPS liability of the typical antipsychotics. The compounds of theinvention show a significant decrease in the number of spontaneouslyactive DA neurons in the A10 area of the brain. However, similar toclozapine and unlike haloperidol, the compounds of the invention do notcause a decrease in the number of DA neurons in the A9 area. This resultstrongly suggests that the compounds should be affective antipsychoticswith little propensity to cause EPS.

CLIMBING MOUSE ASSAY

Antipsychotic activity is determined in the climbing mice assay by amethod similar to those described by P. Protais, et al.,Psychopharmacol., 50:1 (1976) and B. Costall, Eur. J. Pharmacol., 50:39(1978).

Subject CK-1 male mice (23-27 grams) are group-housed under standardlaboratory conditions. The mice are individually placed in wire meshstick cages (4"×10") and are allowed one hour for adaption andexploration of the new environment. Then apomorphine is injectedsubcutaneously at 1.5 mg/kg, a dose causing climbing in all subjects for30 minutes. Compounds to be tested for antipsychotic activity areinjected intraperitoneally or given oral doses at various timeintervals, e.g. 30 minutes, 60 minutes, etc. prior to the apomorphinechallenge at a screening dose of 10-60 mg/kg.

For evaluation of climbing, 3 readings are taken at 10, 20, and 30minutes after apomorphine administration according to the followingscale:

    ______________________________________                                        Climbing Behavior Mice With:                                                                       Score                                                    ______________________________________                                        4 paws on bottom (no climbing)                                                                     0                                                          2 paws on the wall (rearing) 1                                                4 paws on the wall (full climb) 2                                           ______________________________________                                    

Mice consistently climbing before the injection of apomorphine arediscarded.

With full-developed apomorphine climbing, the animals are hanging on tothe cage walls, rather motionless, over long periods of time. Bycontrast, climbs due to mere motor stimulation usually only last a fewseconds.

The climbing scores are individually totaled (maximal score: 6 per mouseover 3 readings) and the total score of the control group (vehicleintraperitioneally, apomorphine subcutaneously) is set to 100%. ED₅₀values with 95% confidence limits, calculated by a linear regressionanalysis, of some of the compounds of the present invention as well asreference standard antipsychotic agents are presented in Table 1.

                  TABLE 1                                                         ______________________________________                                                            CLIMBING MOUSE ASSAY                                        COMPOUND (ED.sub.50 mg/kg, ip)                                              ______________________________________                                        3-[1-(4'-Fluorobenzoyl)propyl-4-                                                                  5.28                                                        piperazine]-6-methoxy-1,2-benzisoxazole                                       3-[1-(4'-Fluorobenzoyl)propyl-4- 0.4                                          piperazinyl]-6-hydroxy-1,2-benzisoxazole                                      hydrobromide                                                                  Clozapine (reference) 8.1                                                     Haloperidol (reference) 0.11                                                ______________________________________                                    

APOMORPHINE STEREOTYPY INHIBITION IN RATS

Purpose

To screen neurolepic compounds which act directly on the dopaminergicsystem by blocking the action of apomorphine on postsynaptic dopaminereceptors (Anden et al., 1967; Ernst, 1967).

Method

The subjects are male Wistar rats (125-250 grams) housed under standardlaboratory conditions. For a primary screen, a group size of six isused. Drug is administered one hour prior to scoring and the animals areplaced in individual clear plastic cages (24×14×13 cm). The controlgroup receives vehicle. Apomorphine is prepared at a concentration of 15mg/10 ml in a 0.003% ascorbic acid stock solution prepared with 30 mg ofascorbic acid in 100 ml of 1% saline to increase the stability of theapomorphine while in solution. Apomorphine is admininistered at a doseof 1.5 mg/kg subcutaneously (s.c.) with a dosage volume of 1 ml/kg 50minutes after test compound or vehicle administration. Stereotypicbehavior is noted 10 minutes later. Stereotypy occurs in a repetitivemanner and is continuous for a 10 second period in the presence of whitenoise. Stereotypic behavior is defined as sniffing, licking or chewingbehavior which occurs in a repetitive manner and is continuous for a10-second period in the presence of white noise. The animal isconsidered protected if this behavior is interrupted. The percenteffectiveness of a drug is determined by the number of animals protectedin each group.

A dose-response is determined in the same manner as a primary screenexcept that a group size of 10 is used and the animals are dosed in arandomized manner. One group receives vehicle. ED₅₀ values forinhibition of stereotypy are calculated by means of Litchfield andWilcoxon Analysis.

Compounds preventing the stereotypy behavioral response to apomorphineare verified to have postsynaptic dopamine receptor antagonistproperties.

References

Anden, N. E., Rubenson, A., Fuxe, K. and Kokfelt, T. evidence fordopamine receptor stimulation by apomorphine. J. Pharm. Pharmacol, 19:627-629, 1967.

Ernst, A. M. Mode of action of apomorphine and dexamphetamine on gnawingcompulsion in rats. Psychopharmacologia (Berl.,) 10:316-323, 1967.

The ED₅₀ values are set forth in Table 2.

                  TABLE 2                                                         ______________________________________                                                         APOMORPHINE STEREOTYPY                                          INHIBITION                                                                   COMPOUND (ED.sub.50 mg/kg, ip or % inhibition)                              ______________________________________                                        3-[1-(4'-Fluorobenzoyl)propyl-4-                                                               0% at 4.0 mg/kg.                                               piperazinyl]-6-hydroxy-1,2-                                                   benzoisoxazole hydrobromide                                                   Clozapine >40 mg/kg.                                                          Haloperidol ED.sub.50 = 0.6 mg/kg, ip.                                      ______________________________________                                    

D₂ /5-HT₂ BINDING ASSAYS ³ H-Spiroperidol Binding to Striatal Membranes(D₂ -Dopaminergic Site) in Rats

Assays were run according to the method of Leysen et al. [1978].Striatal membranes were incubated with ³ H-spiroperidol (0.4 nM) andvarious concentrations of test drug at 37 C. for 10 minutes in 1 ml of0.05 M Tris-HCl buffer, pH 7.7 containing 120 mM NaCl, 5 mM KCl, 2mMCaCl₂, and 1 mM MgCl₂. Nonspecific binding was determined in thepresence of 2μM(+)-butaclamol. Bound ligand was separated by rapidfiltration through Whatman GF/B filters.

³ H-Spiroperidol Binding to Cerebral Cortical membranes (5HT₂ Site) inRats

Assays were performed by a modification of the method of Peroutka andSnyder [1979]. Cortical membranes were incubated with ³ H-spiroperidol(1.5 nM) and various concentrations of test drug at 37° C. for 10minutes in 1 ml of 0.05 M Tris-HCl buffer, pH 7.7 containing 120 mMNaCl, 5 mM KCl, 2 mM CaCl₂, and 1 mM MgCl₂. Nonspecific binding wasdetermined in the presence of 5 μM methysergide. The incubation wasterminated by rapid filtration through Whatman GF/B filters.

The results are set forth in Table 3.

                  TABLE 3                                                         ______________________________________                                        COMPOUND         D.sub.2 IC.sub.50                                                                      5-HT.sub.2 IC.sub.50                                                                    D.sub.2 /5-HT.sub.2                       ______________________________________                                        3-[1-(4'-Fluorobenzoyl)-propyl-4-                                                               0.24 μM                                                                            0.045 μM                                                                             5.3                                         piperazinyl]-6-hydroxy-1,2-                                                   benzisoxazole hydrobromide                                                    Clozapine  0.83 μM 0.05 μM 17                                           Haloperidol 0.018 μM 0.17 μM 0.1                                      ______________________________________                                    

DOPAMINE NEURON SAMPLING

Dopamine Neuron Sampling. Male Wistar rats (280-360 grams) were used inthis procedure. They were housed for at least 48 hours in aclimate-controlled vivarium with food and water continuously available.Each rat was initially anesthetized with chloral hydrate (400 mg/kg ip)and maintained with additional injections as needed throughout theexperiment. The animal was mounted in a stereotaxic apparatus (Kopf,model 900). The cranium was exposed., cleaned of connective tissue anddried. The skull overlying both the substantia nigra [A9:anterior (A)3000-3400 microns, lateral (L) 1800-2400 microns from lambda)] and theventral tegmental area (Al 0: A 3000-3400 microns, L 400-1000 micronsfrom lambda)⁴⁷ was removed. Using the dura as a point of reference, amicropipette driven by a hydraulic microdrive was lowered through theopening in the skull at vertical 6000-8500 microns. Spontaneously firingdopamine neurons within both the substantia nigra and the ventraltegmental areas were counted by lowering the electrode into twelveseparate tracks (each track separated from the other by 200 microns) ineach region. The sequence of the tracks was kept constant, forming ablock of tissue which could be repoducibly located from animal toanimal.

Extracellular neuronal signals were sampled using a single barrelmicropipette approximately one micron at its tip, and filled with 2 MNaCl saturated with 1% pontamine sky blue dye. The in vitro impedance ofthis pipet (measured with a Winston Electronics Co., BL-1000 MicroElectrode Tester) was between 5 and 10 megaohms. Electrical potentialswere passed through a high-impedance preamplifier and the signal wassent to a window discriminator (WPI model 121) which convertedpotentials above background noise levels to discrete pulses of fixedamplitude and duration. Only cells whose electrophysiologicalcharacteristics matched those previously established for midbraindopamine neurons were counted. In an anesthetized rat, a neuron wasconsidered to be dopaminergic if it displayed a triphasicpostive-negative-postive spike profile of 0.4 to 1.5 microvoltsamplitude and 2.5 milliseconds duration, firing in an irregular patternof 3 to 9 Hz with occasional bursts characterized by progressivelydecreasing spike amplitude and increasing spike duration.

At the end of each experiment, the location of the last recorded tracktip was marked by passing 25 microampere cathodal current through therecording micropipette barrel for 15 minutes in order to deposit a spotof dye. The rat was sacrificed; the brain was then removed, dissectedand frozen on a bed of dry ice. Frozen serial sections (20 microns inwidth) were cut, mounted, and stained with cresyl violet and examinedusing a light microscope.

Animals pretreated with vehicle prior to neuronal sampling served ascontrols. Compounds were prepared as percent base. Each compound wassuspended in distilled water and one drop of Tween 80, and keptconstantly agitated during dosing. All compounds were delivered at adosage volume of 1 mg/kg by the intraperitoneal route. For animals usedin the chronic single-unit, dopamine neuron sampling assay, thecompounds were administered once a day for 21 days, and dopamine neuronsampling was begun two hours after the last dose on the 21st day. Drugtreatment groups were compared to vehicle groups with a one-way ANOVAwith a post hoc Neuman-Keuls analysis for significance.

The results are set forth in Table 4.

                  TABLE 4                                                         ______________________________________                                        CHRONIC SINGLE DOPAMINE NEURON SAMPLING IN RATS                                                      % Change in                                                                             % Change in                                    Compound A10 region A9 region                                               ______________________________________                                        3-[1-(4'-Fluorobenzoyl)-propyl-4-                                                                -44.9     +14                                                piperazinyl]-6-hydroxy-1,2-                                                   benzisoxazole hydrobromide at 20                                              mg/kg, ip.                                                                    Clozapine -79 +37                                                             (atypical reference drug)                                                     Haloperidol -35 -30                                                           (atypical reference drug)                                                   ______________________________________                                    

Antipsychotic response is achieved when compounds of the presentinvention are administered to a subject requiring such treatment as aneffective oral, parenteral, or intravenous dose of from 0.01 to 50 mg/kgof body weight per day. It is to be understood, however, that for anyparticular subject, specific dosage regimens should be adjustedaccording to the individual need and the professional judgment of theperson administering or supervising the administration of the aforesaidcompound. It is to be further under stood that the dosages set forthherein are exemplary only and they do not, to any extent, limit thescope or practice of the invention.

Effective amounts of the compounds of the present invention can beadministered to a subject by any one of several methods, for example,orally as in capsules or tablets, parenterally in the form of sterilesolutions or suspensions, and in some cases intravenously in the form ofsterile solutions.

The compounds of the present invention, while effective themselves, canbe formulated and administered in the form of their pharmaceuticallyacceptable addition salts for purposes of stability, convenience ofcrystallization, increased solubility, and the like. Preferredpharmaceutically acceptable addition salts include salts of mineralacids, for example, hydrochloric acid, sulfuric acid, nitric acid, andthe like; salts of monobasic carboxylic acids, for example, acetic acid,propionic acid, and the like, salts of dibasic carboxylic acids, forexample, maleic acid, fumaric acid, and the like; and salts of tribasiccarboxylic acids, such as carboxysuccinic acid, citric acid, and thelike.

Effective quantities of the compounds of the invention can beadministered orally, for example, with an inert diluent or with anedible carrier. They can be enclosed in gelatin capsules or compressedinto tablets. For the purposes of oral therapeutic administration,compounds of the invention can be incorporated with an excipient andused in the form of tablets, troches, capsules, elixirs, suspensions,syrups, wafers, chewing gums, and the like. These preparations shouldcontain at least 0.5% of active compound of the invention, but can bevaried depending upon the particular form and can conveniently bebetween 4% to about 70% of the weight of the unit. The amount of activecompound in such a composition is such that a suitable dosage will beobtained. Preferred compositions and preparations according to thepresent invention are prepared so that an oral dosage unit form containsbetween 1.0-300 milligrams of the active compound of the invention.

Tablets, pills, capsules, troches, and the like can also contain thefollowing ingredients: a binder, such as microcrystalline cellulose, gumtragacanth, or gelatin; an excipient, such as starch or lactose, adisintegrating agent such as alginic acid, Primogel, corn starch, andthe like; a lubricant such as magnesium stearate or Sterores; a glidantsuch as colloidal silicon dioxide; and a sweetening agent such assucrose; or saccarin, or a flavoring agent, such as peppermint, methylsalicylate, or orange flavoring. When the dosage unit form is a capsule,it can contain, in addition to materials of the above type, a liquidcarrier such as a fatty oil. Other dosage unit forms can contain variousmaterials that modify the physical form of the dosage unit, for example,as coatings. Thus, tablets or pills can be coated with sugar, shellac,or other enteric coating agents. A syrup can contain, in addition to theactive compounds, sucrose as a sweetening agent and certainperservatives, dyes, colorings, and flavors. Materials used in preparingthese various compositions should be pharmaceutically pure and non-toxicin the amounts used.

For the purpose of parenteral therapeutic administrations, the activecompound of the invention can be incorporated into a solution orsuspension. These preparations should contain at least 0.1% of activecompound, but can be varied between 0.5 and about 50% of the weightthereof. The amount of active compounds in such compositions is suchthat a suitable dosage will be obtained. Preferred compositions andpreparations according to the present invention are prepared so that aparenteral dosage unit contains between 0.5 to 100 milligrams of activecompound.

Solutions or suspensions can also include the following components: asterile diluent, such as water for injection, saline solution, fixedoils, polyethylene glycols, glycerine, propylene glycol, or othersynthetic solvents; antibacterial agents such as benzyl alcohol ormethyl parabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates, citrates, or phosphates, and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parenteral preparationcan be enclosed in ampules, disposable syringes, or multiple dose vialsmade of glass or plastic.

The highly lipophilic esters, amides, carbonates and carbamates of thepresent invention are capable of sustained release in mammals for aperiod of several days or from about one to four weeks when formulatedand administered as depot preparations, as for example, when injected ina properly selected pharmaceutically acceptable oil. The preferred oilsare of vegetable origin such as sesame oil, cottonseed oil, corn oil,coconut oil, soybean oil, olive oil and the like, or they are syntheticesters of fatty acids and polyfunctional alcohols such as glycerol orpropylene glycol.

The depot compositions of the present invention are prepared bydissolving or suspending a highly lipophilic ester, amide, carbonate orcarbamate of the instant invention in a pharmaceutically acceptable oilunder sterile conditions. The oil is selected so as to obtain a releaseof the active ingredient over a desired period of time. The appropriateoil may easily be determined by consulting the prior art, or withoutundue experimentation by one skilled in the art.

An appropriate dose of a compound in accordance with this embodiment ofthe invention is from about 0.01 to 10 mg/kg of body weight perinjection. Preferably, the depot formulations of this invention areadministered as unit dose preparations comprising about 0.5 to 5.0 ml ofa 0.1 to 20% weight/weight solution of compound in the oil. It is to beunderstood that the doses set forth herein are exemplary only and thatthey do not, to any extent, limit the scope or practice of theinvention.

Representative examples of compounds of the invention and ofintermediates used in their synthesis are set forth in Table 5. Theexamples are for illustrative purposes only and are not to be construedas limiting the invention. All temperatures are given in degreesCentigrade (°C.) unless indicated otherwise.

                                      TABLE 5                                     __________________________________________________________________________    1  STR11##                                                                       -                                                                          Ex. #                                                                            X           n R                      HW Z                                  __________________________________________________________________________       1b 6-OCH.sub.3 1                                                                                                      2  -- O ##                            - 2 6-OH 1                                                                                                            2  -- O ##                            - 3 6-OH 1                                                                                                            2  HBr O #                            - 4 6-OC(═O)O(CH.sub.2).sub.5 CH.sub.3 1                                                                          2  -- O ##                            - 5 6-OC(═O)adamantyl 1                                                                                           2  -- O ##                            - 6 6-OC(═O)(CH.sub.2).sub.8 CH.sub.3 1                                                                           2  -- O ##                            - 7 6-OC(═O)NH(CH.sub.2).sub.3 CH.sub.3 1                                                                         2  -- O ##                            - 8 6-OCH.sub.3 2 H -- O                                                      -  9c 6-OCH.sub.3 1                                                                                                   2  -- NH #                            -  9e 6-OH 1                                                                                                          2  HCl NCH.sub.3                   __________________________________________________________________________

EXAMPLES Example 13-[1-(4'-Fluorobenzoyl)propyl-4-piperazinyl]-6methoxy-1,2-benzisoxazole

a. 6-Methoxy-3-(1-piperazinyl)-1,2-benzisoxazole hemihydrate

A mixture of 3-chloro-6-methoxy-1,2-benzisoxazole (3.0 g) and piperazine(6.0 g) was heated to 140° C. over 4 hours in a sealed tube and thencooled to room temperature. The contents of the tube were dissolved inMeOH and further diluted with EtOAc (IL). The precipitate was filteredand the filtrate dried over MgSO₄ and concentrated in vacuo. Flashchromatography (silica gel) eluting with 30% MeOH/EtOAc provided aresidue upon evaporation (3.6 g, m.p. 79-80 C.).

ANALYSIS: Calculated for C₁₂ H₁₅ N₃ O₂ 0.5H₂ O: 59.490%C 6.65%H 17.34%NFound: 59.25%C 6.28%H 17.30%N

b.3-[1-(4'-Fluorobenzoyl)propyl-4-piperazinyl]-6-methoxy-1,2-benzisoxazole

To a stirred solution of 6-methoxy-3-(1-piperazinyl)-1,2-benzisoxazole(5.0 g, 21.4 mmol) in acetonitrile (25 ml) was added K₂ CO₃ (3.6 g, 25.7mmol), KI (0.4 g, 2.1 mmol) and 4-chloro-4'-fluorobutyrophenone (5.2 g,25.7 mmol) under N₂. The reaction was heated at reflux for 5 hours andallowed to cool to room temperature. The material was diluted withEtOAc, washed with water and brine, dried with MgSO₄, and concentratedin vacuo. The material was flashed chromatographed (silica gel) elutingwith 3:2 EtOAc/heptane affording the pure free base of the product.

ANALYSIS: Calculated for C₂₂ H₂₄ N₃ O₃ F: 66.48%C 6.09%H 10.57%N Found:66.32%C 6.00%H 10.45%N

Example 23-[1-(4'-Fluorobenzoyl)propyl-4-piperazinyl]-6hydroxy-1,2-benzisoxazole

A solution of3-[1-(4'-fluorobenzoyl)propyl-4-piperazinyl]-6-methoxy-1,2-benzisoxazole(3.5 g, 8.8 mmol) and 48% hydrobromic acid was heated at 120° C. for 4hours. The reaction was neutralized with saturated Na₂ CO₃ solution,extracted with EtOAc, and the organic phase was dried (MgSO₄) andconcentrated in vacuo. Flash column chromatography (silica gel) elutingwith 5% MeOH/CH₂ Cl₂, concentration of the desired fractions andrecrystallization from EtOAc provided the product as an off-white solid(0.5 g, 15%, m.p. 181-182° C.).

ANALYSIS: Calculated for C₂₁ H₂₂ N₃ O₃ F: 65.78%C 5.78%H 10.96%N Found:65.52%C 5.89%H 10.76%N

Example 33-[1-(4'-Fluorobenzoyl)propyl-4-piperazinyl]-6hydroxy-1,2-benzisoxazolehydrobromide

A solution of ethereal hydrobromic acid was added to a solution of3-[1-(4'-fluorobenzoyl)propyl-4-piperazinyl]-6-hydroxy-1,2-benzisoxazole(0.31 g, 0.8 mmol) in 50% CH₃ CN/EtOAc and chilled to 0° C. for 1 hour.The precipitate was filtered under N₂ and dried in vacuo to afford thehydrobromide salt as a white solid (0.3 g, 81%, m.p. 260-261° C.).

ANALYSIS: Calculated for C₂₁ H₂₂ N₃ O₃ F HBr: 54.32%C 4.990%H 9.05%NFound: 54.75%C 5.05%H 9.04%N

Example 4 Carbonic acid(3-[4-[4-(4-fluorophenyl)-4-oxo-butyl]-piperazin-1-yl]-1,2-benzisoxazol-6-yl)esterhexyl ester

To a suspension of the compound of Example 3 (7.6 g, 16.4 mmol) in EtOAc(200 ml) was added NaHCO₃ (sat., 100 ml) at room temperature. Afterstirring over night, the solids were removed via filtration and thetwo-phase filtrate was transferred to a separatory funnel. The layerswere separated and the organic phase was dried over Na₂ SO₄. Filtrationand concentration of the filtrate gave 2.9 g (47%) of the compound ofExample 2.

This free amine (0.50 g, 1.31 mmol) was suspended in anhydrous THF (25ml), under nitrogen, and treated with hexyl chloroformate (97%, 0.27 ml,1.57 mmol). Milled potassium carbonate (0.22 g, 1.57 mmol) was thenadded and the reaction mixture was allowed to stir for eighteen hours.The solids were removed via filtration and washed with DCM. The combinedfiltrates were concentrated to give the crude product which was purifiedvia flash column chromatography (silica gel, ethyl acetate).Concentration of the desired fractions gave 0.51 g (76%) of the productas a light brown solid, m.p. 77-80° C.

ANALYSIS: Calculated for C₂₈ H₃₄ FN₃ O₅ : 65.74%C 6.70%H 8.21%N Found:65.80%C 6.74%H 8.04%N

Example 5 Adamantane-1-carboxylic acid3-[4-[4-(4-fluorophenyl)-4-oxo-butyl]-piperazin-1-yl]-1,2-benzisoxazol-6-ylester

The compound of Example 2 (0.50 g, 1.31 mmol) was suspended inacetonitrile (15 ml), under nitrogen, and treated with K₂ CO₃ (0.20 g,1.44 mmol). 1-Adamantanecarbonyl chloride (0.30 g, 1.44 mmol) was thenadded and the reaction mixture was allowed to stir for sixty hours. Thesolids were removed via filtration and washed with DCM. The combinedfiltrates were concentrated to give the crude product which was purifiedvia flash column chromatography (silica gel, ethyl acetate).Concentration of the desired fractions gave 0.52 g (73%) of the productas a white solid, m.p. 157-158° C.

ANALYSIS: Calculated for C₃₂ H₃₆ FN₃ O₄ : 70.44%C 6.65%H 7.70%N Found:70.29%C 6.62%H 7.54%N

Example 6 Decanoic acid3-[4-[4-(4-fluorophenyl)-4-oxo-butyl]-piperazin-1-yl]-1,2-benzisoxazol-6-ylester

The compound of Example 2 (0.60 g, 1.57 mmol) was suspended inacetonitrile (15 ml), under nitrogen, and treated with K₂ CO₃ (0.24 g,1.73 mmol). Decanoyl chloride (0.36 ml, 1.73 mmol) was then added andthe reaction mixture was allowed to stir for sixty hours. The solidswere removed via filtration and washed with DCM. The combined filtrateswere concentrated to give 0.80 g (95%) of the desired product as a brownsolid, m.p. 69-71° C.

ANALYSIS: Calculated for C₃₁ H₄₀ FN₃ O₄ 69.25%C 7.50%H 7.82%N Found:69.28%C 7.71%H 7.76%N

Example 7 Butyl carbamic acid3-[4-[4-(4-fluorophenyl)-4-oxo-butyl]-piperazin-1-yl]-1,2-benzisoxazol-6-ylester

The compound of Example 2 (0.50 g, 1.31 mmol) was suspended in anhydrousTHF (25 ml), under nitrogen, and treated with butyl isocyanate (0.18 ml,1.57 mmol). Milled potassium carbonate (0.22 g, 1.57 mmol) was thenadded and the reaction mixture was allowed to stir for eighteen hours.The solids were removed via filtration and washed with DCM. The combinedfiltrates were concentrated to give the crude product which was purifiedvia flash column chromatography (silica gel, ethyl acetate).Concentration of the desired fractions gave 0.40 g (63%) of the productas a light brown solid, m.p. 137-141° C.

ANALYSIS: Calculated for C₂₆ H₃₁ FN₄ O₄ : 64.72%C 6.48%H 11.61%N Found:64.29%C 6.83%H 11.77%N

Example 8 3-(1-homopiperazinyl)-6-methoxy-1,2-benzisoxazole

3-Chloro-6-methoxy-1,2-benzisoxazole (5.0 g, 27.2 mmol) andhomopiperazine (8.2 g, 81.6 mmol) were combined and mechanically stirredunder N₂ at 140° C. for 45 minutes. The reaction mixture was cooled toroom temperature, dissolved with EtOAc (500 ml), and the solution waswashed with water, brine, dried over MgSO₄, and concentrated in vacuo.Flash column chromatography (silica gel, 20% MeOH/CH₂ Cl₂) provided theproduct (2.0 g, m.p. 74-75° C.

ANALYSIS: Calculated for C₁₃ H₁₇ N₃ O₂ : 63.14%C 6.93%H 16.99%N Found:62.88%C 6.85%H 16.81%N

Example 91-(4Fluorophenyl)-4-[4-[6-hydroxy-1-methyl-1H-indazol-3-yl]-piperazin-1-yl]-butan-1-onehydrochloride hydrate

a.4-[4-[N-(p-Toluenesulfonylhydazono)-2-fluoro-4-methoxyphenylmethyl]-piperazin-1-yl]-1-(4-fluorophenyl)butan-1-one

To a stirred solution of alpha-chloro-2-fluoro4-methoxy benzaldehyde,1-p-toluenesulfonylhydrazone (4.6 g, 12.8 mmol) in chloroform (20 ml)was added a solution of 1-(4-fluorophenyl)4-piperazin-1-yl-butan-1-one(3.2 g, 12.8 mmol) in chloroform (20 ml) and allowed to stir at ambienttemperature under nitrogen for 1 hour. The reaction was diluted withmethylene chloride, washed with water, dried over Na₂ SO₄, andconcentrated in vacuo. The residue was flash chromatographed elutingwith 3:2 CH₂ Cl₂ /EtOAc to afford the product, 2.5 g, mp=66-67 C.

ANALYSIS: Calculated for C₂₉ H₃₂ N₄ O₄ F₂ S: 61.04%C 5.65%H 9.82%NFound: 60.74%C 5.53%H 9.69%N

b.1-(4-Fluorophenyl)-4-[4-[6-methoxy-1-toluene-4-sulfonyl)-1H-indazol-3-yl]-piperazin-1-yl]-butan-1-one

To a stirred solution of the compound of Example 9a (2.5 g, 4.4 mmol) inN,N-dimethylformamide (10 ml) was added K₂ CO₃ (1.2 g, 8.8 mmol) underN₂. The reaction was heated to 90 C. for 3 hours. The reaction mixturewas then cooled, diluted with with ethyl acetate, washed with brine (6times), dried over Na₂ SO₄, and concentrated in vacuo. The residue wasflash chromatographed eluting with 3:2 CH₂ Cl₂ /EtOAc to afford theproduct, 2.3 g, mp=120-121 C.

ANALYSIS Calculated for C₂₉ H₃ 1 N₄ O₄ FS: 63.26%C 5.67%H 10. 17%NFound: 62.99%C 5.71%H 9.86%N

c.1(4-Fluorophenyl)-4-[4-[6-methoxy)-1H-indazol-3-yl]-piperazin-1-yl]-butan-1-one

A mixture of the compound of Example 9b (1 g, 1.8 mmol) and 30 ml of 12M hydrochloric acid was heated at 90 C for 1 hour under nitrogen. Thereaction mixture was cooled, diluted with EtOAc, and neutralized withNa₂ CO₃ (sat'd). The organic layer was separated and the aqueous layerwas extracted again with EtOAc. The organic layers were combined, driedover Na₂ SO₄ and evaporated to afford 0.65 g of the desired product,mp=157-162 C.

d.1-(4-Fluorophenyl)-4-[4-[6-methoxy)-1-methyl-1H-indazol-3-yl]-piperazin-1-yl]-butan-1-one

To a mixture of the compound of Example 9c (0.45 g, 1.13 mmol) andpotassium hydroxide (0.19 g, 3.4 mmol) in 40 ml of acetone, there wasadded dimethylsulfate (0.14 g, 0.11 ml, 1.13 mmol) and the mixture wasrefluxed for three hours. The reaction mixture was cooled, diluted withmethylene chloride and washed with brine. The organic layer was driedover Na₂ SO₄ and concentrated in vacuo. The residue was flashchromatographed. Elution with 5% MeOH/CH₂ Cl₂ gave 0.4 g of the product,mp=103-104 C.

e.1-(4-Fluorophenyl)-4-[4-[6-hydroxy)-1-methyl-1H-indazol-3-yl]-piperazin-1-yl]-butan-1-onehydrochloride hydrate

To 48% hydrobromic acid (20 ml) was added the compound of Example 9d(0.40 g, 1.0 mmol) and the mixture was heated to 110° C. under N2 forfour (4) hours. Then the mixture was cooled and diluted with EtOAc andneutralized with saturated Na2CO3 solution and extracted with additionalEtOAc. The organic layers were combined, dried over Na2SO4 andconcentrated in vacuo. The residue was flash chromatographed (silicagel, 3% MeOH/CH2Cl2 to yield a white solid which was dissolved in EtOAcand acidified with ethereal hydrochloride acid to afford the salt, 0.30g, mp=243-244° C.

ANALYSIS Calculated for C₂₂ H₂₅ N₄ O₂ F.HCl.H₂ O: 58.60%C 6.26%H 12.40%NFound: 58.60%C 6.06%H 12.36%N

It should be understood that this specification and examples are setforth by way of illustration and not limitation and that variousmodifications and changes may be made without departing from the spiritand scope of the present invention as defined by the appended claims.

We claim:
 1. A compound of the formula ##STR21## wherein X is --OH,OC(═O)(C₁ -C₁₈)alkyl, --OC(═O)NH(C₁ -C₁₈)alkyl, --OC(═O)O(C₁ -C₁₈)alkylor --OC(═O)--(C₃ -C₁₂)cycloalkyl;Y is hydrogen, halogen,trifluoromethyl, (C₁ -C₆)alkoxy, cyano or nitro; m is 1, 2, 3, or 4; andp is 1 or 2; or the pharmaceutically acceptable addition salts thereof.2. The compound of claim 1 of the formula: ##STR22## wherein X is --OH,OC(═O)(C₁ -C₁₈)alkyl, --OC(═O)NH(C₁ -C₁₈)alkyl, --OC(═O)O(C₁ -C₁₈)alkylor --OC(═O)--(C₃ -C₁₂)cycloalkyl;Y is hydrogen or halogen m is 1, 2, 3,or 4; and p is 1 or the pharmaceutically acceptable addition saltsthereof.
 3. The compound of claim 2 wherein m is 3 and Y is 4-fluoro. 4.The compound of claim 3 wherein X is 6-hydroxy, 6-OC(═O)NHbutyl,6-OC(═O)Ohexyl, 6-OC(═O)nonyl, or 6-OC(═O)adamantyl; and itspharmaceutically acceptable acid addition salts.
 5. A process forpreparing a compound of the formula: ##STR23## wherein X is --OH,OC(═O)(C₁ -C₁₈)alkyl, --OC(═O)(C₆ -C₁₂)aryl, --OC(═O)(C₆ -C₂)alkyl(C₆-C₁₀)aryl, OC(═O)NH(C₁ -C₁₈)alkyl, --OC(═O)(C₃ -C₁₂)alkyl(C₃-C₈)cycloakyl, --OC(═O)O(C₁ -C₁₈)alkyl or --OC(═O)--(C₃-C₁₂)cycloalkyl;Y is H, halogen, trifluoromethyl, (C₁ -C₆)alkoxy, cyanoor nitro; m is 1, 2, 3, or 4; n is 1 or 2; and p is 1 or 2; or thepharmaceutically acceptable addition salts thereof comprising reacting acompound of the formula: ##STR24## wherein X and n are defined as above,with a compound of the formula: ##STR25## wherein halo is Br or Cl, andY, m and p are defined as above, in a polar non-protic organic solventin the presence of a base and a catalyst.
 6. A process for preparing acompound of the formula: ##STR26## wherein Y is H, halogen,trifluoromethyl, (C₁ -C₆)alkoxy, cyano or nitro;m is 1, 2, 3 or 4; n is1 or 2; and p is 1 or 2; or the pharmaceutically acceptable acidaddition salts thereof, comprising heating a compound of the formula:##STR27## wherein X is --OC(═O)(C₁ -C₁₈)alkyl, --OC(═O)(C₆ --C₁₀)aryl,--OC(═O)(C₁ -C₁₂)alkyl(C₆ -C₁₀)aryl, --OC(═O)NH(C₁ -C₁₈)alkyl,--OC(═O)(C₁ -C₁₂)alkyl(C₃ -C₈)cycloalkyl, --OC(═O)O(C₁ -C₁₈)alkyl, or--OC(═O)--(C₃ -C₁₂)cycloalkyl, and Y, m, n and p are defined as above,with 48% HBr.
 7. A method of treating psychosis in a mammal in need ofpsychosis treatment which comprises administering to such a mammal apsychosis treating effective amount of a compound of claim
 1. 8. Apsychosis treating pharmaceutical composition comprising an adjuvant andas the active ingredient, a psychosis treating effective amount of acompound of claim
 1. 9. A method of providing an anti-psychotic effectof from about one to four weeks which comprises administering to amammal a composition according to claim 8 wherein the effective amountof the composition is sufficient to produce an anti-psychotic effect offrom about one to four weeks.
 10. A depot pharmaceutical composition fortreating psychosis comprising an adjuvant and as the active ingredient,a psychosis effective amount of a compound of the formula ##STR28##wherein X is --OC(═O)(C₁ -C₁₈)alkyl, --OC(═O)NH(C₁ -C₁₈)alkyl,--OC(═O)O(C₁ -C₁₈)alkyl or --OC(═O)--(C₃ -C₁₂)cycloalkyl;Y is hydrogenor halogen m is 1, 2, 3, or 4; and p is 1; or the pharmaceuticallyacceptable addition salts thereof.